Genome-wide association Scan of dental caries in the permanent dentition

BMC Oral Health

Mary L Marazita⁶  Eleanor Feingold⁵  Daniel E Weeks⁵  Daniel W McNeil^1,11  Richard Crout⁷  Robert J Weyant^1,12  Deborah E Polk⁹  Elizabeth W Pugh⁴  Kimberly F Doheny⁴  Sarah C Nelson^1,10  Cathy C Laurie^1,10  David R Crosslin^1,10  Frank B Hu³  Marilyn C Cornelis³  Eric Boerwinkle¹  James Beck⁸  Myoung-Keun Lee²  Karen T Cuenco⁶  Ida Anjomshoaa²  Jacqueline Noel²  Alexandre R Vieira²  Ferdouse Begum⁵  Zhen Zeng⁶  John R Shaffer⁶  Xiaojing Wang² 

[1] IMM Center for Human Genetics and Division of Epidemiology, School of Public Health, University of Texas, Houston, Texas, 77030, USA;Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA;Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, 02115, USA;Center for Inherited Disease Research, School of Medicine, Johns Hopkins University Baltimore, Baltimore, MD, 21205, USA;Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA;Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA;Department of Periodontics, West Virginia University School of Dentistry, Morgantown, WV, 26506, USA;UNC School of Dentistry, North Carolina Oral Health Institute, Chapel Hill, NC, 27599, USA;Department of Behavioral and Community Health Sciences, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA;Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA;Dental Practice and Rural Health, West Virginia University School of Dentistry, Morgantown, WV, 26506, USA;Department of Dental Public Health, University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA, 15261, USA

关键词: Genomics;    Permanent dentition;    Genome wide association;    Genetics;    Dental caries;   

Others  :  1126231
DOI  :  10.1186/1472-6831-12-57

 received in 2012-06-13, accepted in 2012-11-28,  发布年份 2012

【 摘 要 】

Background

Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults.

Methods

Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries.

Results

Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens.

Conclusions

As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Beltran-Aguilar ED, Barker LK, Canto MT, Dye BA, Gooch BF, Griffin SO, Hyman J, Jaramillo F, Kingman A, Nowjack-Raymer R, et al.: Surveillance for dental caries, dental sealants, tooth retention, edentulism, and enamel fluorosis–United States, 1988–1994 and 1999–2002. Morb Mortal Wkly Rep Surveill Summ 2005, 54(3):1-43.
• [2]Bretz WA, Corby PM, Melo MR, Coelho MQ, Costa SM, Robinson M, Schork NJ, Drewnowski A, Hart TC: Heritability estimates for dental caries and sucrose sweetness preference.[see comment]. Arch Oral Biol 2006, 51(12):1156-1160.
• [3]Bretz WA, Corby PM, Schork NJ, Robinson MT, Coelho M, Costa S, Melo Filho MR, Weyant RJ, Hart TC: Longitudinal analysis of heritability for dental caries traits. J Dent Res 2005, 84(11):1047-1051.
• [4]Boraas JC, Messer LB, Till MJ: A genetic contribution to dental caries, occlusion, and morphology as demonstrated by twins reared apart. J Dent Res 1988, 67(9):1150-1155.
• [5]Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, McNeil DW, Marazita ML: Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 2010, 44(3):277-284.
• [6]Wendell S, Wang X, Brown M, Cooper ME, DeSensi RS, Weyant RJ, Crout R, McNeil DW, Marazita ML: Taste genes associated with dental caries. J Dent Res 2010, 89(11):1198-1202.
• [7]Kang SW, Yoon I, Lee HW, Cho J: Association between AMELX polymorphisms and dental caries in Koreans. Oral Dis 2011, 17(4):399-406.
• [8]Deeley K, Letra A, Rose EK, Brandon CA, Resick JM, Marazita ML, Vieira AR: Possible association of amelogenin to high caries experience in a Guatemalan-Mayan population. Caries Res 2008, 42(1):8-13.
• [9]Slayton RL, Cooper ME, Marazita ML: Tuftelin, mutans streptococci, and dental caries susceptibility. J Dent Res 2005, 84(8):711-714.
• [10]De Soet JJ, van Gemert-Schriks MC, Laine ML, van Amerongen WE, Morre SA, van Winkelhoff AJ: Host and microbiological factors related to dental caries development. Caries Res 2008, 42(5):340-347.
• [11]Shaffer JR, Wang X, Feingold E, Lee M, Begum F, Weeks DE, Cuenco KT, Barmada MM, Wendell SK, Crosslin DR, et al.: Genome-wide association scan for childhood caries implicates novel genes. J Dent Res 2011, 90(12):1457-1462.
• [12]Polk DE, Weyant RJ, Crout RJ, McNeil DW, Tarter RE, Thomas JG, Marazita ML: Study protocol of the Center for Oral Health Research in Appalachia (COHRA) etiology study. BMC Oral Health 2008, 6(3):8-18.
• [13]Anjomshoaa I, Cooper ME, Vieira AR: Caries is Associated with Asthma and Epilepsy. Eur J Dentistry 2009, 3(4):297-303.
• [14]Cornelis MC, Agrawal A, Cole JW, Hansel NN, Barnes KC, Beaty TH, Bennett SN, Bierut LJ, Boerwinkle E, Doheny KF, et al.: The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet Epidemiol 2010, 34(4):364-372.
• [15]Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM, Offenbacher S: Relationship of periodontal disease to carotid artery intima-media wall thickness: the atherosclerosis risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol 2001, 21(11):1816-1822.
• [16]Borrell LN, Beck JD, Heiss G: Socioeconomic disadvantage and periodontal disease: the Dental Atherosclerosis Risk in Communities study. Am J Public Health 2006, 96(2):332-339.
• [17]Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K: Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol 2008, 9(6):550-558.
• [18]Qi L, Cornelis MC, Kraft P, Stanya KJ, Linda Kao WH, Pankow JS, Dupuis J, Florez JC, Fox CS, Pare G, et al.: Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 2010, 19(13):2706-2715.
• [19]Drury TF, Horowitz AM, Ismail AI, Maertens MP, Rozier RG, Selwitz RH: Diagnosing and reporting early childhood caries for research purposes. A report of a workshop sponsored by the National Institute of Dental and Craniofacial Research, the Health Resources and Services Administration, and the Health Care Financing Administration. J Public Health Dent 1999, 59(3):192-197.
• [20]Bennett SN, Caporaso N, Fitzpatrick AL, Agrawal A, Barnes K, Boyd HA, Cornelis MC, Hansel NN, Heiss G, Heit JA, et al.: Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience. Genet Epidemiol 2011, 35(3):159-173.
• [21]Laurie CC, Doheny KF, Mirel DB, Pugh EW, Bierut LJ, Bhangale T, Boehm F, Caporaso NE, Cornelis MC, Edenberg HJ, et al.: Quality control and quality assurance in genotypic data for genome-wide association studies. Genet Epidemiol 2010, 34(6):591-602.
• [22]Browning BL, Browning SR: A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 2009, 84(2):210-223.
• [23]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81(3):559-575.
• [24]Willer CJ, Li Y, Abecasis GR: METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010, 26(17):2190-2191.
• [25]Gamazon ER, Zhang W, Konkashbaev A, Duan S, Kistner EO, Nicolae DL, Dolan ME, Cox NJ: SCAN: SNP and copy number annotation. Bioinformatics 2010, 26(2):259-262.
• [26]Ge D, Zhang K, Need AC, Martin O, Fellay J, Urban TJ, Telenti A, Goldstein DB: WGAViewer: software for genomic annotation of whole genome association studies. Genome Res 2008, 18(4):640-643.
• [27]Barrett JC: Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009, 2009(10):pdb ip71.
• [28]Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ: LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010, 26(18):2336-2337.
• [29]Simon S, Smith AJ, Berdal A, Lumley PJ, Cooper PR: The MAP kinase pathway is involved in odontoblast stimulation via p38 phosphorylation. J Endod 2010, 36(2):256-259.
• [30]Botero TM, Son JS, Vodopyanov D, Hasegawa M, Shelburne CE, Nor JE: MAPK signaling is required for LPS-induced VEGF in pulp stem cells. J Dent Res 2010, 89(3):264-269.
• [31]Takaoka A, Tanaka N, Mitani Y, Miyazaki T, Fujii H, Sato M, Kovarik P, Decker T, Schlessinger J, Taniguchi T: Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-gamma, but not IFN-alpha, signaling. EMBO J 1999, 18(9):2480-2488.
• [32]Pandey P, Avraham S, Kumar S, Nakazawa A, Place A, Ghanem L, Rana A, Kumar V, Majumder PK, Avraham H, et al.: Activation of p38 mitogen-activated protein kinase by PYK2/related adhesion focal tyrosine kinase-dependent mechanism. J Biol Chem 1999, 274(15):10140-10144.
• [33]Nakashima M: Bone morphogenetic proteins in dentin regeneration for potential use in endodontic therapy. Cytokine Growth Factor Rev 2005, 16(3):369-376.
• [34]About I, Laurent-Maquin D, Lendahl U, Mitsiadis TA: Nestin expression in embryonic and adult human teeth under normal and pathological conditions. Am J Pathol 2000, 157(1):287-295.
• [35]Chung IH, Choung PH, Ryu HJ, Kang YH, Choung HW, Chung JH, Choung YH: Regulating the role of bone morphogenetic protein 4 in tooth bioengineering. J Oral Maxillofac Surg 2007, 65(3):501-507.
• [36]Schlessinger K, Hall A, Tolwinski N: Wnt signaling pathways meet Rho GTPases. Genes Dev 2009, 23(3):265-277.
• [37]Liu F, Chu EY, Watt B, Zhang Y, Gallant NM, Andl T, Yang SH, Lu MM, Piccolo S, Schmidt-Ullrich R, et al.: Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis. Dev Biol 2008, 313(1):210-224.
• [38]Tao W, Pennica D, Xu L, Kalejta RF, Levine AJ: Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev 2001, 15(14):1796-1807.
• [39]Le Goff C, Somerville RP, Kesteloot F, Powell K, Birk DE, Colige AC, Apte SS: Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis. Development 2006, 133(8):1587-1596.
• [40]Mitsiadis TA, Angeli I, James C, Lendahl U, Sharpe PT: Role of Islet1 in the patterning of murine dentition. Development 2003, 130(18):4451-4460.
• [41]Kouskoura T, Fragou N, Alexiou M, John N, Sommer L, Graf D, Katsaros C, Mitsiadis TA: The genetic basis of craniofacial and dental abnormalities. Schweiz Monatsschr Zahnmed 2011, 121(7–8):636-646.
• [42]Horst OV, Horst JA, Samudrala R, Dale BA: Caries induced cytokine network in the odontoblast layer of human teeth. BMC Immunol 2011, 12:9. BioMed Central Full Text
• [43]Veerayutthwilai O, Byers MR, Pham TT, Darveau RP, Dale BA: Differential regulation of immune responses by odontoblasts. Oral Microbiol Immunol 2007, 22(1):5-13.
• [44]Mutoh N, Tani-Ishii N, Tsukinoki K, Chieda K, Watanabe K: Expression of toll-like receptor 2 and 4 in dental pulp. J Endod 2007, 33(10):1183-1186.
• [45]Takahashi K, Sugi Y, Hosono A, Kaminogawa S: Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol 2009, 183(10):6522-6529.
• [46]Horst OV, Tompkins KA, Coats SR, Braham PH, Darveau RP, Dale BA: TGF-beta1 Inhibits TLR-mediated odontoblast responses to oral bacteria. J Dent Res 2009, 88(4):333-338.
• [47]Geller F, Feenstra B, Zhang H, Shaffer JR, Hansen T, Esserlind AL, Boyd HA, Nohr EA, Timpson NJ, Fatemifar G, et al.: Genome-wide association study identifies four loci associated with eruption of permanent teeth. PLoS Genet 2011, 7(9):e1002275.
• [48]Vieira AR, Marazita ML, Goldstein-McHenry T: Genome-wide scan finds suggestive caries loci. J Dent Res 2008, 87(5):435-439.
• [49]Sandberg GE, Sundberg HE, Fjellstrom CA, Wikblad KF: Type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. Diabetes Res Clin Pract 2000, 50(1):27-34.
• [50]Collin HL, Uusitupa M, Niskanen L, Koivisto AM, Markkanen H, Meurman JH: Caries in patients with non-insulin-dependent diabetes mellitus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998, 85(6):680-685.
• [51]Hintao J, Teanpaisan R, Chongsuvivatwong V, Dahlen G, Rattarasarn C: Root surface and coronal caries in adults with type 2 diabetes mellitus. Community Dent Oral Epidemiol 2007, 35(4):302-309.